Vibeke Andrée Larsen

Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study

BACKGROUND Extracranial arterial dilatation has been hypothesised to be the cause of pain in patients who have migraine without aura. To test that hypothesis, we aimed to measure extracranial and intracranial arteries during attacks of migraine without aura. METHODS In this cross-sectional study, we recruited patients aged 18-60 years from the Danish Headache Centre and via announcements on a Danish website. We did magnetic resonance angiography during spontaneous unilateral migraine attacks. Primary endpoints were difference in circumference of extracranial and intracranial arterial segments comparing attack and attack-free days and the pain and the non-pain side. The extracranial arterial segments measured were the external carotid (ECA), the superficial temporal (STA), the middle meningeal (MMA), and the cervical part of the internal carotid (ICAcervical) arteries. The intracranial arterial segments were the cavernous (ICAcavernous) and cerebral (ICAcerebral) parts of the internal carotid, the middle cerebral (MCA), and the basilar (BA) arteries. This study is registered at Clinicaltrials.gov, number NCT01471314. FINDINGS Between Oct 12, 2010, and Feb 8, 2012, we recruited 78 patients, of whom 19 women had a scan during migraine and were included in the final analysis. On migraine compared with non-migraine days, we detected no statistically significant dilatation of the extracranial arteries on the pain side (ECA, mean difference 1·2% [95% CI -5·7 to 8·2] p=0·985, STA 3·6% [-3·7 to 11·0] p=0·532, MMA 1·7% [-1·7 to 5·2] p=0·341, and ICAcervical 2·3% [-0·3 to 4·9] p=0·093); the intracranial arteries were more dilated during attacks (MCA, 13·0% [6·4 to 19·6] p=0·001, ICAcerebral 11·5% [5·6 to 17·3] p=0·0004, and ICAcavernous 11·4% [5·3 to 17·5] p=0·001), except for the BA (1·6% [-2·7 to 5·9] p=0·621). Compared with the non-pain side, during attacks we detected dilatation on the pain side of the intracranial arteries (MCA, mean difference 10·5% [0·7-20·3] p=0·044, ICAcerebral (14·4% [4·6-24·1] p=0·013), and ICAcavernous (9·1% [3·9-14·4] p=0·003) but not of the extracranial arteries (ECA, 2·1% [-3·8 to 9·2] p=0·238, STA, 3·6% [-3·7 to 10·8] p=0·525, MMA, 2·7% [-1·3 to 5·6] p=0·531, and ICAcervical, 5·0% [-0·5 to 10·4] p=0·119). INTERPRETATION Migraine pain was not accompanied by extracranial arterial dilatation, and by only slight intracranial dilatation. Future migraine research should focus on the peripheral and central pain pathways rather than simple arterial dilatation. FUNDING University of Copenhagen, the Lundbeck Foundation, the Research Foundation of the Capital Region of Denmark, Danish Council for Independent Research-Medical Sciences, and the Novo Nordisk Foundation.

The microheterogeneity of α1-acid glycoprotein in inflammatory lung disease, cancer of the lung and normal health

The concentration of alpha 1-acid glycoprotein (AGP, orosomucoid) was measured in sera from 19 patients with primary squamous cell carcinoma of the lung, 16 patients with an inflammatory lung disease and 17 persons with normal health. All sera were further subjected to crossed immuno-affinoelectrophoresis with addition of Con A in the first dimension and sugar in the second dimension. The distribution of AGP into four microheterogeneity forms, which were the result of this analysis, was estimated by measuring the area under the precipitation curve. The microheterogeneity patterns of AGP in the three groups were significantly different from each other (p less than 0.001). The total concentration of AGP in the two groups of patients was significantly different from the concentration in the healthy group (p less than 0.001).

Magnetic resonance angiography shows dilatation of the middle cerebral artery after infusion of glyceryl trinitrate in healthy volunteers

Previous studies have reported dilatation of the middle cerebral artery (MCA) during acute glyceryl trinitrate (GTN)-induced headache, using imaging techniques such as transcranial Doppler (TCD), positron emission tomography (PET) and single photon emission computerized tomography (SPECT). In the present study we aimed to evaluate whether magnetic resonance angiography (MRA) may be used to examine the effect of GTN on the MCA, with respect to changes in diameter and cross-sectional area in healthy volunteers. In addition, we wanted to determine the intra- and inter-observer variation of the method. In a randomized, double blind, crossover study 12 healthy volunteers received intravenous infusion of GTN (0.5 μg/kg/min for 20 min) or placebo. Using 1.5 Tesla MRA, we recorded changes in the diameter and cross-sectional area of MCA before, during and after infusion of GTN. The MRA images were evaluated by two blinded, independent observers/neuroradiologists. The primary endpoints were the differences in the AUC for diameter and cross-sectional area of the MCA between the two experimental conditions and the intra- and inter-observer variation. The areas under the curve (AUC) of the MCA diameter and cross-sectional area were significantly greater after GTN than after placebo (P < 0.05). The intra-observer variation (day-to-day) at baseline was 8.3% and 10.9% for the two observers. The mean inter-observer variation of the cross-sectional MCA area was 15.5% and for the diameter measurements 8%. The present study shows that the MRA method gives a reliable semi-quantitative index of the vascular changes in the intra-cerebral arteries after infusion of GTN and may be useful for headache research.

Interhemispheric differences of fMRI responses to visual stimuli in patients with side-fixed migraine aura

Migraine sufferers with aura often report photosensitivity and visual discomfort outside of attacks and many consider bright or flickering light an attack‐precipitating factor. The nature of this visual hypersensitivity and its relation to the underlying pathophysiology of the migraine aura is unknown. Using fMRI measurements during visual stimulation we examined the visual cortical responsiveness of patients with migraine with aura. We applied a within‐patient design by assessing functional interhemispheric differences in patients consistently experiencing visual aura in the same visual hemifield. We recruited 20 patients with frequent side‐fixed visual aura attacks (≥90% of auras occurring in the same visual hemifield) and 20 age and sex matched healthy controls and compared the fMRI blood oxygenation level dependent (BOLD) responses to visual stimulation between symptomatic and asymptomatic hemispheres during the interictal phase and between migraine patients and controls. BOLD responses were selectively increased in the symptomatic hemispheres. This was found in the inferior parietal lobule (P = 0.002), the inferior frontal gyrus (P = 0.003), and the superior parietal lobule (P = 0.017). The affected cortical areas comprise a visually driven functional network involved in oculomotor control, guidance of movement, motion perception, visual attention, and visual spatial memory. The patients also had significantly increased response in the same cortical areas when compared to controls (P < 0.05). We discovered a lateralized alteration of a visually driven functional network in patients with side‐fixed aura. These findings suggest a hyperexcitability of the visual system in the interictal phase of migraine with visual aura. Hum Brain Mapp 35:2714–2723, 2014.

Hemiplegic migraine aura begins with cerebral hypoperfusion: imaging in the acute phase.

(Headache 2011;51:1289‐1296)

Phase 1 dose-escalation study of the antiplacental growth factor monoclonal antibody RO5323441 combined with bevacizumab in patients with recurrent glioblastoma

BACKGROUND We conducted a phase 1 dose-escalation study of RO5323441, a novel antiplacental growth factor (PlGF) monoclonal antibody, to establish the recommended dose for use with bevacizumab and to investigate the pharmacokinetics, pharmacodynamics, safety/tolerability, and preliminary clinical efficacy of the combination. METHODS Twenty-two participants with histologically confirmed glioblastoma in first relapse were treated every 2 weeks with RO5323441 (625 mg, 1250 mg, or 2500 mg) plus bevacizumab (10 mg/kg). A standard 3 + 3 dose-escalation trial design was used. RESULTS RO5323441 combined with bevacizumab was generally well tolerated, and the maximum tolerated dose was not reached. Two participants experienced dose-limiting toxicities (grade 3 meningitis associated with spinal fluid leak [1250 mg] and grade 3 cerebral infarction [2500 mg]). Common adverse events included hypertension (14 participants, 64%), headache (12 participants, 55%), dysphonia (11 participants, 50%) and fatigue (6 participants, 27%).The pharmacokinetics of RO5323441 were linear, over-the-dose range, and bevacizumab exposure was unaffected by RO5323441 coadministration. Modulation of plasmatic angiogenic proteins, with increases in VEGFA and decreases in FLT4, was observed. Dynamic contrast-enhanced/diffusion-weighted MRI revealed large decreases in vascular parameters that were maintained through the dosing period. Combination therapy achieved an overall response rate of 22.7%, including one complete response, and median progression-free and overall survival of 3.5 and 8.5 months, respectively. CONCLUSION The toxicity profile of RO5323441 plus bevacizumab was acceptable and manageable. The observed clinical activity of the combination does not appear to improve on that obtained with single-agent bevacizumab in patients with recurrent glioblastoma.

A Doppler waveform index to characterize hepatic vein velocity pattern and evaluate hepatic fibrosis.

To describe a Doppler waveform index representing the hepatic vein flow velocity pattern and to examine its relationship to the degree of hepatic fibrosis.

Hepatic Transit Time of Ultrasound Contrast in Biopsy Characterized Liver Disease

Purpose: To study the hepatic transit time of an ultrasound contrast agent in patients with liver disease, and to evaluate the mechanism(s) of the well-established shorter cubital vein to hepatic vein transit time in cirrhosis. Material and Methods: Thirty-four patients scheduled for Menghini liver biopsy were studied by ultrasound after injection of 2.5 g Levovist (Schering, Berlin, Germany) into an arm vein. The time from injection until the first appearance of contrast echoes in the hepatic artery and hepatic veins was registered. Hepatic transit time was the difference between the two. Results: Biopsy showed cirrhosis in 9 patients, other diffuse hepatic pathology in 23 patients, and normal liver in 2 patients. Mean hepatic vein arrival time was earlier in cirrhosis than in other liver disease (19.4 s versus 26.0 s; P = 0.013), and hepatic transit time was shorter (6.6 s versus 11.6 s; P = 0.024). A hepatic transit time <10 s was found in all patients with cirrhosis, but also in 10 of 23 patients with other liver pathology. Conclusion: Hepatic transit time measurement could not be used to distinguish between cirrhosis and other hepatic pathology, but a transit time = 10 s excluded cirrhosis. The earlier hepatic vein arrival time in cirrhosis is apparently mainly caused by intrahepatic shunting rather than by early arrival of contrast to the liver.

Short-term myeloid growth factor mediated expansion of bone marrow haemopoiesis| studied by localized magnetic resonance proton spectroscopy

Summary. Previously we have shown that short‐term myeloid growth factor priming of haemopoiesis prior to bone marrow harvest increased the yield of myeloid progenitors in the graft. The present study is intended to investigate the expansion of haemopoiesis by volume selective proton magnetic resonance spectroscopy (MRS).

Sensory migraine aura is not associated with structural grey matter abnormalities.

Migraine with aura (MA) is characterized by cortical dysfunction. Frequent aura attacks may alter cerebral cortical structure in patients, or structural grey matter abnormalities may predispose MA patients to aura attacks. In the present study we aimed to investigate cerebral grey matter structure in a large group of MA patients with and without sensory aura (i.e. gradually developing, transient unilateral sensory disturbances). We included 60 patients suffering from migraine with typical visual aura and 60 individually age and sex-matched controls. Twenty-nine of the patients additionally experienced sensory aura regularly. We analysed high-resolution structural MR images using two complimentary approaches and compared patients with and without sensory aura. Patients were also compared to controls. We found no differences of grey matter density or cortical thickness between patients with and without sensory aura and no differences for the cortical visual areas between patients and controls. The somatosensory cortex was thinner in patients (1.92 mm vs. 1.96 mm, P = 0.043) and the anterior cingulate cortex of patients had a decreased grey matter density (P = 0.039) compared to controls. These differences were not correlated to the clinical characteristics. Our results suggest that sensory migraine aura is not associated with altered grey matter structure and that patients with visual aura have normal cortical structure of areas involved in visual processing. The observed decreased grey matter volume of the cingulate gyrus in patients compared to controls have previously been reported in migraine with and without aura, but also in a wide range of other neurologic and psychiatric disorders. Most likely, this finding reflects general bias between patients and healthy controls.